Abstract Host inflammatory immune responses to oral microbiota are tightly regulated by multiple pro-inflammatory and anti-inflammatory mechanisms. The balance of there two activities ensures a state of immune homeostasis which is critical for protecting against microbial invasion and avoiding subsequent collateral tissue damages. To limit the ferocity of inflammation, a number of established pathways exist that dampen the innate immune response. Our recent publication has demonstrated a novel role for serum- and glucocorticoid- inducible kinase 1 (SGK1), a serine/threonine kinase associated with the PI3K pathway, in restraining the production of E. coil LPS-mediated pro-inflammatory cytokine production in human monocytes. Preliminary data for this application show for the first time that SGK1 is phospho-activated in human monocytes in response to challenge with multiple oral bacteria. In addition, using P. gingivalis, a well-established model oral organism for the investigation of host-pathogen interactions in the periodontium, we show that inhibition of SGK1 robustly enhances the production of pro-inflammatory cytokines (TNF, IL-12, IL-6, IL-1?, IL-8) and reduces IL-10 levels, a result also confirmed by using Cre-loxP-mediated SGK1 knockout mice. Moreover, the anti-inflammatory role for SGK1 was validated by our preliminary in vivo evidence showing that systemic administration of the SGK1 inhibitor, EMD638683, elevated infiltration of neutrophils and macrophages into the gingival tissues and aggravated the severity of alveolar bone resorption in mice orally infected with P. gingivalis. Thus, we have identified a novel role for SGK1 as a negative regulator of inflammation, and propose that stimulation of this endogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis-induced tissue destruction. The specific hypothesis to be tested in this application is that in the context of P. gingivalis challenge, SGK1 constrains the production of pro-inflammatory cytokines; down-regulates recruitment of inflammatory cells to the periodontium; and in turn protects against alveolar bone loss through downstream modification of inflammatory signaling molecules including Nedd4-2, MKP-1, and TAK1, which ultimately converge on NF-?B. We will challenge this hypothesis with three specific Aims: (i) To characterize SGK1 as an innate immune suppressor of inflammatory responses in vitro; (ii) To elucidate the signaling mechanisms by which SGK1 controls host inflammatory responses; and (iii) To establish the in vivo relevance of SGK1 in the control of host inflammation using mouse subcutaneous chamber and alveolar bone loss models. Successful completion of these studies will characterize, for the first time, the anti-inflammatory function of SGK1 in host inflammatory responses to P. gingivalis, and elucidate the novel anti-inflammatory signaling network mediated by the SGK1-MKP1 module in the control of the inflammation progression. In the long term, this work could pave the way for the development of novel anti-inflammatory agents targeting SGK1 or MKP-1 to ameliorate or prevent not only P. gingivalis-induced tissue destruction, but other inflammatory disorders. Such an approach has relevance both for periodontal disease and for chronic inflammatory conditions in general.